Stem Cells: Progress Towards "the Cure"?

For the last three years, Project Inform has spearheaded a renewed call for research that seeks to find a real cure for HIV disease, rather than settling for lifetime maintenance therapy on drugs. A case study from the Medical University of Berlin reported at CROI 2008 offered intriguing results from a stem cell transplant, an approach that was tried before but without success.

Previous stem cell transplant programs primarily sought to replenish the immune system with new cells. After the transplant, these programs typically counted on using anti-HIV therapy to protect the new immune cells.

However in this case, a person who had been living with HIV since 1995 underwent treatment with stem cells for a relapse of acute myeloid leukemia, a cancerous growth of a type of white blood cell. Since the patient was HIV-positive, researchers sought out a stem cell donor whose cells lacked the CCR5 receptor that HIV commonly uses to get into immune cells.

Research shows that people who lack this receptor are highly resistant to HIV infection. We inherit two copies of the gene that makes this receptor, one from each of our parents. If a copy from one parent is defective, a person generally becomes a slow progressor if infected by HIV because of the lower number of functional CCR5 receptors. If copies from both parents are defective, a person is highly resistant to HIV infection or, if infected, typically becomes a long-term non-progressor.

Only a small percentage of people, usually of European descent, have this fortunate genetic trait. The importance of the CCR5 receptor is well shown in studies of the drug Selzentry (maraviroc), which blocks the receptor and slows HIV reproduction. This patient's own cells had the usual amount of the CCR5 receptor, and the strain of HIV in his blood was the type that used the receptor. The German researchers hoped that by using stem cells that lacked the ability to make the receptor, the newly restored immune cells might better resist HIV infection and replication.

Researchers stopped the patient's HIV regimen at the day of the stem cell transplant and have not restarted it. Ongoing studies 145 days after the transplant showed that the patient's mucosal CD4+ cells now lack the CCR5 receptor. More importantly, starting 61 days after the transplant, the patient's HIV level fell below the limit of detection and has remained undetectable since then. Similarly, they can no longer find evidence of pro-viral DNA in peripheral blood, bone marrow or rectal mucosa.

Pro-viral DNA is HIV genetic information that has been incorporated into a cell's own DNA, and is capable of producing new virus. These tests remain negative out to nearly 300 days (285 days as of CROI), despite the absence of any HIV drug treatment since the stem cell transplant. Before the transplant, the patient required a normal 3-drug regimen.

The researchers are making only the most modest statements about what this means, saying, "this finding provides a possible therapeutic option for HIV-infected patients." Several physicians and researchers we spoke with were much more enthusiastic. At the very least, this strongly reinforces the importance of blocking, or eliminating, the CCR5 receptor.

Few potential donors could offer stem cells that not only match the patient's but also lack the CCR5 receptor, though there may be ways to clone such cells. Gene therapy could perhaps be used to alter stem cells. For now, follow-up of this case is important to see when, if ever, there is a return of HIV replication. The German researcher we spoke with said that it would perhaps be possible to find HIV in the patient using other methods, but as long as there was no evidence of ongoing replication on HIV RNA tests, they would not restart HIV therapy.

This is another one of the kind of "one step at a time" approaches that we hope will one day lead to an outright cure of HIV infection, a state in which people who were once actively infected can remain "HIV undetectable" without any ongoing use of therapy. We urge other researchers to replicate or build upon this impressive case study, and we salute the patient and his doctors for taking this bold approach to treating HIV disease.